Alcohol and the risk of all-cause death, atrial fibrillation, ventricular arrhythmia, and sudden cardiac arrest

The risk of having atrial fibrillation (AF) is associated with alcohol intake. However, it is not clear whether sudden cardiac arrest (SCA) and ventricular arrhythmia (VA) including ventricular tachycardia, flutter, or fibrillation have similar associations with alcohol. We aimed to evaluate the association of alcohol intake with all-cause death, new-onset AF, VA, and SCA using single cohort with a sufficient sample size. A total of 3,990,373 people without a prior history of AF, VAs, or SCA was enrolled in this study based on nationwide health check-up in 2009. We classified the participants into four groups according to weekly alcohol consumption, and evaluated the association of alcohol consumption with each outcome. We observed a significant association between mild (hazard ratio [HR] = 0.826; 95% confidence interval [CI] = 0.815–0.838) to moderate (HR = 0.930; 95% CI = 0.912–0.947) drinking with decreased risk of all-cause mortality. However heavy drinking (HR = 1.108; 95% CI = 1.087–1.129) was associated with increased all-cause death. The risk of new-onset AF was significantly associated with moderate (HR = 1.129; 95% CI = 1.097–1.161) and heavy (HR = 1.298; 95% CI = 1.261–1.337) drinking. However, the risk of SCA showed negative association with all degrees of alcohol intake: 20% (HR = 0.803; 95% CI = 0.769–0.839), 15% (HR = 0.853; 95% CI = 0.806–0.902), and 8% (HR = 0.918; 95% CI = 0.866–0.974) lower risk for mild, moderate, and heavy drinkers, respectively. Mild drinking was associated with reduced risk of VA with moderate and heavy drinking having no associations. In conclusion, the association between alcohol and various outcomes in this study were heterogeneous. Alcohol might have different influences on various cardiac disorders.


Alcohol intake
This study uses two parameters included in the questionnaire of the national health screening: the number of days per week a respondent drinks and the amount a respondent consumes in a drinking session.We defined a standardized cup as a different volume for each type of alcoholic beverage but can hold a similar amount of alcohol (ethanol).For example, a 220 mL-sized standard cup for beer and a 50 mL-sized cup for Soju (a traditional Korean alcohol) can be calculated to hold about 8 g of alcohol each 15 .Based on the exact amount of alcohol intake measured, the total amounts of alcohol consumed per week were calculated, and participants were classified into four groups: (i) non-drinkers: 0 g per week; (ii) mild drinkers: less than 105 g per week; (iii) moderate drinkers: less than 210 g per week; (iv) heavy drinkers: equal to or more than 210 g per week (Supplementary Table S1).

Definitions
The diagnoses of AF, VA (VT, VFL, VF), and SCA were based on the record of International Classification of Disease, 10th revision codes (ICD-10) in the K-NHIS database.The exact ICD-10 diagnostic codes for diseases related to this study are described in Supplementary Table S2.The strategy of ICD-10 code-based diagnosis is validated in our multiple publications 6,7,16,17 .The incidence of new-onset AF, VT, VFL, VF, or SCA was calculated as the number of newly diagnosed cases of each disease per 1,000 patient-years of follow-up.

Statistical analysis
Comparison between continuous variables was performed by Student's t-test and ANOVA, the results of which are presented as mean ± standard deviation.Chi-square test was used to make a comparison between categorical values, and the results are described as percentile values.The hazard ratio (HR) and 95% confidence interval (CI) were analyzed by multivariate Cox regression analysis.Multivariate model 1 is adjusted for age and sex; model 2 for model 1 plus body-mass index (BMI), smoking status, regular exercise habit, and income level; model 3 for model 2 plus hypertension, diabetes mellitus, dyslipidemia, and CKD; and model 4 for model 3 plus history of heart failure and thyroid disease.Covariates that showed significance difference among groups stratified by alcohol consumption amount were included in the model.Variables that were associated with the risk of SCA in our prior work was also included in the model 18 .For all multivariate adjustments, non-drinkers were set as the reference group.All significance tests were two-tailed, and p-values less than 0.05 were considered statistically significant.

Study participants
A flowchart describing the enrollment of study participants is presented in Fig. 1.After exclusion by age, prior diagnosis, or missing data, 3,990,373 people were included in this study.Participants were classified into nondrinkers, mild drinkers, moderate drinkers, and heavy drinkers, and their baseline demographics are summarized in Table 1.Non-drinkers were more often older, female, and smoked less.In addition, they had lower BMI, waist circumference, and blood pressure; higher low-density lipoprotein (LDL); less regular exercise habits; and higher prevalence of CKD, heart failure, and thyroid disease (Table 1).

Ventricular arrhythmias
The association between alcohol and VAs was different from that of AF.In comparison with non-drinkers, mild drinkers showed significantly lower risk of VA (HR = 0.87; 95% CI = 0.82-0.92;p < 0.01; Table 2 and Fig. 2).www.nature.com/scientificreports/Moderate drinking and heavy drinking were associated with numerically, but not statistically, lower risk of VA (Table 2 and Fig. 2).Risk factors associated with increased risk of VA were old age, male sex, current smoker, lack of regular exercise, hypertension, diabetes mellitus, dyslipidemia, and CKD (Fig. 3c).

Subgroup analysis
The interaction between alcohol consumption and sex on each outcome was evaluated (Table 3).Increased risk of AF in drinkers was more pronounced in males.However, females were more vulnerable to alcohol in terms of all-cause death.No remarkable interactions were observed between alcohol and sex in ventricular arrhythmias and SCA.Age also did not show any meaningful interactions with alcohol consumption in all outcomes.

Discussion
In this study, we analyzed the relationship between the amount of alcohol intake and all-cause mortality, AF, VA (VT, VFL, or VF), and SCA.The principal findings of this study are as follows.(i) The association between alcohol consumption and risk of all-cause mortality is U-shaped.Compared to non-drinkers, mild to moderate drinkers had lower risk, while heavy drinkers had higher risk.(ii) Moderate to heavy drinkers had a significantly increased risk of AF compared with non-drinkers.(iii) Alcohol intake, regardless of amount, was associated with lower risk of SCA.(iv) Mild drinkers had lower risk of VA compared with non-drinkers.The strong points of our study are a large sample size, adjustment of various covariates, and analysis of all-cause mortality, AF, VA, and SCA in the same cohort.In this way, we were able to reveal the different influence of alcohol on AF vs. VA and SCA.

Alcohol and cardiac arrhythmias
The association between alcohol and AF is demonstrated in multiple prior studies 14,15 .The lower risk of all-cause mortality in mild to moderate drinkers was also observed in other observational studies 12 .Our study showed similar results in a different ethnic group with a larger sample size utilizing nationwide health insurance data.It has long been discussed that alcohol intake and the risk of VA and SCA may have a specific relationship, but this has not been clarified 19 .Prior studies of VA with limited sample sizes showed inconsistent results 11,20,21 .One study of patients with myocardial infarction who did not receive thrombolytic therapy stated that frequency of drinking was not associated with an increased risk of VA 20 , while another study of patients without cardiovascular disease concluded that heavy consumption of alcohol is a major risk factor for VA 21 .Using the UK Biobank cohort, a recent study gathered a much larger and more generalized population 11 .The study reported a U-shaped relationship such that those who drank less than 208 g of alcohol per week (in the current study, mild and moderate drinkers) had less risk of SCA, while the conclusion for VAs was not statistically significant 11 .In our study, not only mild to moderate drinkers, but also heavy drinkers had a significantly lower risk of SCA.For VAs, mild drinkers had a significantly lower risk compared with non-drinkers.Moderate and heavy drinkers had numerically, but not statistically significant, lower risk of VAs.To our knowledge, this is the study with the largest sample size (n = 3,990,373) to evaluate the associations between alcohol and various cardiac disorders simultaneously.

Biological mechanism
Alcohol consumption can cause pathophysiological changes to the heart, such as alterations in the atrial effective refractory period or the autonomic nervous system 15,22,23 .Elevation in blood pressure, obesity, and direct toxic effects on cardiomyocytes are other explanations for the association between alcohol consumption and increased risk of new-onset AF 15,24,25 .www.nature.com/scientificreports/Ventricular arrhythmias can be initiated by various factors, but the main cause is acute ischemia of the heart or pre-existing ischemia-related scar 26 .Coronary artery disease is also a main cause of SCA.It is widely perceived that a moderate alcohol intake can have a protective effect on coronary artery disease 27,28 , and one systematic review reported that the risk significantly decreases when consuming more than 30 g of alcohol per day 28 , a criterion classified as heavy drinking (> 210 g per week) in the current study.This effect can be explained by changes in cholesterol levels and coagulation factors, both related to atherosclerosis and thrombogenesis in the coronary arteries.Intake of alcohol is associated with higher synthesis and slower decrease in high-density lipoprotein (HDL) level, thereby maintaining an upregulated level of HDL 29,30 .Furthermore, our study revealed an inverse linear association between amount of alcohol intake and LDL level (Table 1).High HDL and low LDL can have a prohibitory effect on the underlying inflammatory process of atherosclerosis; as a result, the risk of coronary artery disease might decrease as well as the risk of VAs and SCA.Although investigated at a cellular level, alcohol is also proven to have an effect on upregulating expression and synthesis of fibrinolytic proteins such as tissue plasminogen activator, which can prohibit the formation of thrombi 31,32 .

Clinical implications
Ventricular arrhythmia is strongly connected to the risk of SCA, a major socioeconomic burden.Due to a narrow therapeutic window, most SCA events have low chance of neurologically intact survival 33 .Atrial fibrillation is another major burden for the general population since its prevalence is up to 2% 34 .Primary prevention of both diseases will have a significant impact on public health.Although alcohol consumption was associated with significantly lower risk of SCA, the risk of new-onset AF was significantly increased.Furthermore, significantly increased risk of all-cause death was observed in the heavy-drinker group.Mild to moderate intake of alcohol might have benefits in terms of prevention of SCA and all-cause death.However, due to potential bias originating from retrospective analysis, heterogeneous effect of alcohol on individuals, and non-cardiac hazardous effects such as carcinogenesis, we cannot conclude whether mild to moderate intake of alcohol will be beneficial for public health 35,36 .Regarding the risk of new-onset AF, cessation or reducing alcohol intake might be helpful for the prevention in the general population.

Limitations
This study was based on the database of K-NHIS, which exclusively comprises East Asian ethnicity, so it is necessary to consider ethnic differences when applying the result to other ethnic groups.Also, not just one, but multiple measurements of alcohol consumption habits should be considered in future studies since changes in alcohol intake habits can have independent association with cardiac arrhythmia and SCA.Since this study was based on a claim database, unmeasured confounders and coding inaccuracies might exist.Despite vigorous efforts to adjust various confounders in the multivariable models, residual confounders can exist.Diagnosis of AF, VT, and VF was based on reports of relevant ICD-10 codes and electrocardiography documentation was not possible.

Conclusion
New-onset AF and SCA (including VAs) showed different directions of association with alcohol intake.Opposite association with alcohol intake suggests that AF and SCA (including VAs) have different pathophysiology.All-cause death was lower in mild to moderate drinkers but higher in heavy drinkers.Since the risk of SCA in heavy drinkers was higher than in mild and moderate drinkers, despite being lower than in non-drinkers, heavy drinking should be avoided.

Figure 1 .
Figure 1.Flow of the study.

Figure 2 .
Figure 2. Influence of alcohol consumption Incidence is per 1,000 person*year follow-up.AF: atrial fibrillation; CI: confidence interval; HR: hazard ratio; VA: ventricular arrhythmia; VF: ventricular fibrillation; VFL: ventricular flutter; VT: ventricular tachycardia; SCA: sudden cardiac arrest Alcohol consumption demonstrated different associations with all-cause mortality, atrial fibrillation, ventricular arrhythmias, and sudden cardiac arrest.HRs are adjusted for age, sex, body mass index, smoking status, regular exercise, income level, hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, heart failure, and thyroid disease.

Figure 3 .
Figure 3. Risk factors for all-cause death, AF, VA, and SCA.Male, non-smoker, no regular exercise, nonhypertensive, non-diabetic, and no dyslipidemia were set as reference values for each set of comparison.For values regarding income, low income (lowest quintile) was set as the reference for all-cause mortality, while high income was set as the reference for the rest of the diseases in interest.

Table 2 .
Alcohol and risk of all-cause mortality, AF, VA, and SCA.Values are expressed as hazard ratio with its 95% confidence interval.Multivariate model 1: adjusted for age and sex.Multivariate model 2: model 1 plus body mass index, smoking status, regular exercise habit, and income level.Multivariate model 3: model 2 plus hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease.Multivariate model 4: model 3 plus history of heart failure and thyroid disease.Multivariate model 5: model 4 plus history of liver cirrhosis and cancer diagnosis.

Table 3 .
Subgroup analysis.Values are expressed as hazard ratio with its 95% confidence interval.AF: atrial fibrillation; VT: ventricular tachycardia; VF: ventricular fibrillation; VFL: ventricular flutter; SCA: sudden cardiac arrest.Hazard ratios are adjusted for age, sex, body mass index, smoking status, regular exercise habit, income level, hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, heart failure, and thyroid disease.